One-pot Synthesis of Polysubstituted Dihydro-2- oxypyrroles …jacr.kiau.ac.ir/article_527186_4f621a6e88516fd2b8485bca4... · 2020-06-23 · low-cost, eco-friendly, one-pot, simple

Journal of Applied Chemical Research, 11, 1, 115-123 (2017)

Journal of App l ied Chemical Research

www.jacr.k iau.ac. i r

One-pot Synthesis of Polysubstituted Dihydro-2-oxypyrroles Catalyzed by Vanadium (V) oxide

Farzaneh Mohamadpour1, Malek Taher Maghsoodlou1*, Reza Heydari1, Mojtaba Lashkari2 1Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran

2Faculty of Science, Velayat University, Iranshahr, Iran)Received 24 Jul. 2016; Final version received 21 Sep. 2016(

Abstract

A mild and efficient synthesis of polysubstituted dihydro-2-oxypyrroles has been developed

for the one-pot, four-component domino condensation of dialkyl acetylenedicarboxylate,

formaldehyde and aromatic amines using Vanadium (V) oxide as the catalyst at ambient

temperature. The use of Vanadium (V) oxide makes this process simple, more convenient,

and environmentally friendly.

Keywords: Vanadium )V( oxide, Dihydro-2-oxypyrrole derivatives, Multi-component

reactions, Eco-friendly.

*Corresponding author: Malek Taher Maghsoodlou, Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, P. O. Box 98135-674 Zahedan, Iran. Tel: +98-541-2446565, Fax: +98-541-2446565. E-mail: [email protected].

IntroductionIn the past few decades, studies in multi-

component reactions (MCRs) [1-5] is an

important goal for organic researches. Because

of their important advantages such as atom-

economy, mild and environmentally-friendly,

low-cost, eco-friendly, one-pot, simple work-

up MCRs is useful tools for the synthesis of

heterocyclic compounds with biological and

pharmaceutical activities such as dihydro-2-

oxypyrroles.

Because of their pharmaceutical and biological

activities, in recent years, the compound with

pyrrole rings such as dihydro-2-oxypyrroles

are an important class of heterocyclic

compounds, such as DNA polymerase

inhibitors [6] , has been used as P1-091 [7] , and

Thiomarinol A4 as antibiotic has pyrrole rings

[8], many of number alkaloids with biological

activities have pyrrole rings [9], human

cytomegalovirus( HCMV) protease [10],

human cytosolic carbonic anhydrase isozymes

[11], CD45 protein tyrosinphosphatase [12],

cardiac cAMPphosphodiestrase [13]. In

addition, these rings have been used HIV

integrase [14], protoporphyrinogen oxidase

M. T. Maghsoodlou et al., J. Appl. Chem. Res., 11, 1, 115-123 (2017)116

and herbicidal [15], modulators of GABAA

receptors [16] and they have also anti- cancer

[17], activities and these rings have been

used as UCS1025A [18] and Oteromycin

[19]. Some example containing heterocyclic

dihydro-2-oxypyrrole rings with biologically

activities have been shown in Figure 1.

NH

OHH

O

O

Oteromycin

NH

O

O

C6H13

OH

Me

MeMe

Me

Pl-o91

N

OHOH O

UCS1025A

OO

H

H

Figure 1. Biologically active compounds with dihydro-2-oxypyrrole rings.

In recent decades, a number of methodologies

for preparation of these compounds have been

reported that is including Lewis and Brønsted

acid catalysts such as I2 [20], NiCl2 [21],

heterogeneous TiO2 nanopowder [22], InCl3

[23], [n-Bu4N][HSO4] [24], Al(H2PO4)3 [25],

AcOH [26], Cu(OAC)2.H2O [27], Oxalic acid

[28], ZrCl4 [29]. Some of these methodologies

have limitations such as toxic and expensive

catalysts, long time reactions, low yields, use of

strongly acidic conditions, difficulty work-up.

Therefore, the study of mild catalysts and how

their effect on environment is an aim in our

recent researches and because of specially

pharmaceutical and biological properties

these compounds, the development of simple

methodology and environmentally safe for

the synthesis of these compounds has become

the most important goal of our researches

and finally, we have been reported vanadium

(V) oxide as an inorganic, mild and efficient

catalyst for the synthesis of polysubstituted

dihydro-2-oxypyrrole through a one-pot four-

component reaction between aromatic amines

(1 and 3), dialkyl acetylenedicarboxylate 2 and

formaldehyde 4 in the presence of vanadium

(V) oxide as an efficient catalyst under ambient

temperature in methanol (Scheme1).

R1 NH2

CO2R2

CO2R2

ArH2NN

OHN

R2O2C

R1

(5 a-l)

O

43

2

1+ +

V2O5(15mol %)

MeOH, r.t.

H

H HH

Ar+

Scheme 1. Synthesis of polysubstituted dihydro-2-oxypyrroles.

M. T. Maghsoodlou et al., J. Appl. Chem. Res., 11, 1, 115-123 (2017) 117

Experimental

General

Melting points and IR spectra all compounds

were determined using an Electro thermal

9100 apparatus and a JASCO FTIR 460

Plus spectrometer. Also, nuclear magnetic

resonance, 1H NMR spectra were recorded on

a Bruker DRX-400 Avance instruments with

CDCl3 as solvent. All reagents and solvents

were purchased from Merck, Fluka and Acros

chemical companies were used without further

purification.

General procedure for preparation of

polysubstituted dihydro-2-oxypyrroles )5a-l(

A mixture of amine 1 (1.0 mmol) and dialkyl

acetylenedicarboxylate 2 (1.0 mmol) was

stirred in MeOH (3 mL) for 15 min. next,

amine 3 (1.0 mmol) and formaldehyde 4 (1.5

mmol) and vanadium (V) oxide (0.027 g)

were added and the reaction was stirred for

appropriate time (Table 3). After completion

of the reaction (by thin layer chromatography

TLC), the mixture was separated with

filtration and the solid washed with ethanol

(3×2 mL) with no column chromatographic

separation to give pure compounds (5a-l).

The catalyst is solvable in ethanol and was

removed from the reaction mixture. All

products were characterized by comparison

of spectroscopic data (FT-IR, 1HNMR).

Spectra data of products are represented

below:

Methyl 4-)4-methoxyphenylamino(-1-)4-

methoxyphenyl(-2, 5-dihydro-5-oxo-1H-pyr-

role-3-carboxylate )5a(

Yellow solid, M.p. 174-176 °C; 1H NMR (400

MHz, CDCl3): δ 3.77 (3H, s, CH3), 3.83 (6H,

s, 2OCH3), 4.50 (2H, s, CH2-N), 6.89 (4H, d,

J=17.6 Hz, ArH), 7.13 (1H, s, ArH), 7.68 (1H,

s, ArH), 8.03 (1H, s, NH).

Ethyl 4-)4-methoxyphenylamino(-1-)4-

methoxyphenyl(-2, 5-dihydro-5-oxo-1H-

pyrrole-3-carboxylate )5b(

Yellow solid, M.p. 150-152 °C; 1H NMR

(400 MHz, CDCl3): δ 1.26 (3H, t, J=7.2Hz,

CH2CH3), 3.83 (6H, s, 2OCH3), 4.23 (2H, q,

J=7.2 Hz, CH2CH3), 4.50 (2H, s, CH2-N), 6.87

(2H, d, J=8.8 Hz, ArH), 6.93 (2H, d, J=8.8 Hz,

ArH), 7.12 (2H, d, J=8.8 Hz, ArH), 7.69 (2H,

d, J=8.8 Hz, ArH), 8.02 (1H, s, NH).

Ethyl 4-)4-chlorophenylamino(-1-)4-chloro-

phenyl( -2,5-dihydro-5-oxo-1H-pyrrole3-car-

boxylate )5d(

Yellow solid, M.p. 169-171°C. IR (KBr)

(kmax, cm-1): 3,320 (NH), 2,991, 1,698,

1,640; 1H NMR (400 MHz, CDCl3): δ 1.29

(3H, t, J=7.2 Hz, OCH2CH3), 4.27 (2H, q,

J=7.2 Hz, OCH2CH3), 4.52 (2H, s, CH2-N),

7.09 (2H, d, J=8.8 Hz, ArH), 7.29 (2H, d, J

= 8.4 Hz, ArH), 7.37 (2H,d,J = 8.8 Hz,ArH),

7.76 (2H,d,J = 8.8 Hz,ArH), 8.07 (1H, s,

NH).


Methyl 4-(4-fluoroyphenylamino)-1-(4-

fluorophenyl)-2, 5-dihydro-5-oxo-1H-pyrrole-

3-carboxylate )5e(


MHz, CDCl3): δ 3.79 (3H, s, OCH3), 4.52 (2H,

s, CH2-N), 7.04 (2H, t, J=8.4 Hz, ArH), 7.08-

7.16 (4H, m, ArH), 7.73-7.79 (2H, m, ArH),

8.05 (1H, s, NH).

Methyl 2,5-dihydro-2-oxo-1-phenyl-3-

)phenylamino(-1H-pyrrole4-carboxylate )5g(

Yellow solid, M.p. 154-156 °C; IR (KBr,

cm−1): ν 3264 (NH), 1692 (C=O), 1641 (C=O); 1H NMR (400 MHz, CDCl3): δ 3.76 (3H, s,

OCH3), 4.57 (2H, s, CH2-N), 7.16-7.23 (4H, m,

ArH), 7.35 (2H, t, J=7.8 Hz, ArH), 7.42 (2H, t,

J=7.8 Hz, ArH), 7.81 (2H, d, J=8.0 Hz, ArH),

8.05 (1H, s, NH).

Ethyl 1-phenyl-3-)phenylamino(-2,5-dihydro-

2-oxo-1H-pyrrole-4-carboxylate )5h(


(400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz,

OCH2CH3), 4.24 (2H, q, J=7.2 Hz, OCH2CH3),

4.44 (2H, s, CH2-N), 7.15-7.23 (4H, m, ArH),

7.35 (2H, d, J=7.6 Hz, ArH), 7.41 (2H, d, J=7.6

Hz, ArH), 7.82 (2H, d, J=7.8 Hz, ArH), 8.01

(1H, s, NH).

Methyl 4-)4-methylphenylamino(-1-)4-

methylphenyl(-2, 5-dihydro-5-oxo-1H-pyrrole-

3-carboxylate )5i(


MHz, CDCl3): 2.36 (3H, s, 2CH3), 3.77 (3H,

s, OCH3), 4.52 (2H, s, CH2-N), 7.06 (2H, d,

J=8.4 Hz, ArH), 7.14 (2H, d, J=8.4 Hz, ArH),

7.21(2H, d, J=8.4 Hz, ArH), 7.68 (2H, d, J=8.8

Hz, ArH), 8.03 (1H, s, NH).

Ethyl 4-)4-methylphenylamino(-1-)4-methyl-

phenyl( -2, 5-dihydro-5-oxo-1H-pyrrole-3-car-

boxylate )5j(


MHz, CDCl3): 1.25 (3H, t, J=7.2 Hz, CH2CH3),

2.37 (6H, s, 2CH3), 4.23 (2H, q, J=7.2 Hz,

2CH2CH3), 4.53 (2H, s, CH2-N),7.06 (2H, d,

J=8.4 Hz, ArH), 7.14 (2H, d, J=8.4 Hz, ArH),

7.21 (2H, d, J=8.4 Hz, ArH), 7.68 (2H, d, J=8.4

Hz, ArH), 8.01 (1H, s, NH).

Methyl 4-)4-bromophenylamino(-1-)4-bromo-

phenyl( 2,5-dihydro-5-oxo-1H-pyrrole-3-car-

boxylate )5k(

Yellow solid, M.p. 173-175 °C; 1HNMR (400

MHz, CDCl3): δ 3.78 (3H, s, OCH3), 4.50 (2H,

s, CH2-N), 7.08 (2H, d, J= 8.8 Hz, ArH), 7.30

(2H, d, J= 8.4 Hz, ArH), 7.35 (2H, d, J=8.8 Hz,

ArH), 7.72 (2H, d, J= 8.8 Hz, ArH), 8.03 (1H,

s, NH).

Ethyl 3-)4-bromophenylamino(-1-)4-bromo-

phenyl( -2,5-dihydro-2-oxo-1H-pyrrole-4-car-

boxylate )5l(


(400 MHz, CDCl3): δ 1.24 (3H, t, J=7.0 Hz,

OCH2CH3), 4.24 (2H, q, J=7.2 Hz, OCH2CH3),


4.49 (2H, s, CH2-N), 7.09 (2H, d, J=8.0 Hz,

ArH), 7.27-7.75 (6H, m, ArH), 8.04 (1H, s, NH).

Results and discussion

The generality of this four condensation

reaction was studied under optimized

conditions and the reaction between aniline,

dimethyl acetylenedicarboxylate (DMAD)

and formaldehyde was investigation as a

model reaction and then the effect of different

amount of catalyst was also studied in this

protocol and in the absence of catalyst, a trace

amount of this product was detected after 12h

(Table 1, entry 1). Good yields were obtained

in the presence of catalyst. The best amount

of catalyst was 15 mol % (0.027 g) (Table 1,

entry 4). The higher amount of catalyst did not

increase the yields products (Table 1, entry 5)

and the results are summarized in Table 1.

Table 1. Optimization of the reaction condition in the presence of different amounts of vanadium (V) oxidea.

O H

HNH2

CO2Me

CO2MeN

ON

MeO2C

H+ +

HH

+ NH2

Isolated Yields (%)ProductTime (h)V2O5 (mol %)Entry

trace5g12Catalyst free1

265g852

455g8103

815g6154

835g6205aReaction conditions: aniline (2.0 mmol), dialkyl acetylenedicarboxylate (1.0 mmol) and formaldehyde (1.5mmol) and catalyst at room temperature.

Also the effect of various solvents was

investigated for this protocol, EtOH, MeOH,

H2O, CH2Cl2, CHCl3, CH3CN and among

these solvents, MeOH was found to be the best

solvent for this methodology and the results are

shown in Table 2 (Table 2, entry 3).


Table 2. Optimization of the reaction condition in the presence of different solvents by using of V2O5 (15 mol%) a.

O H

HNH2

CO2Me

CO2MeN

ON

MeO2C

H+ +

HH

+ NH2

Isolated Yields (%)ProductTime (h)SolventCatalyst (mol%)Entry

395g7Solvent freeV2O51

625g6EtOHV2O52

815g6MeOHV2O53

265g8H2OV2O54

195g8CH2Cl2V2O55

235g8CHCl3V2O56

415g6CH3CNV2O57aReaction conditions: aniline (2.0 mmol), dialkyl acetylenedicarboxylate (1.0 mmol) and formaldehyde (1.5 mmol)and catalyst in various solvents at room temperature.

Finally, we reported vanadium (V) oxide (0.027

g) as a mild an inorganic catalyst for efficient,

environmental benign nature and eco-friendly

one-pot four-component reaction of aromatic

amines, dialkyl acetylenedicarboxylate and

formaldehyde in MeOH as solvent under

ambient temperature.

In order to study of this procedure, we have

synthesis a series of dihydro-2-oxypyrrole

derivatives with the type of aromatic

amines with electron-donating or electron-

withdrawing groups such as Cl, Br, F, Me,

OMe,… and dialkyl acetylenedicarbixylate

with formaldehyde under ambient temperature

in MeOH which gave good to high yields and

the results are shown in Table 3.


Table 3. Synthesis of dihydro-2-oxypyrrole derivatives.

Lit. M.p. °CM.p. °CYield

(%)a

Time

(h)ProductArR2R1Entry

172-175 [19]174-1767865a4-OMe-

C6H4

Me4-OMe-

C6H4

1

152-154 [20]150-1527465b4-OMe-

C6H4

Et4-OMe-

C6H4

2

171-173 [19]171-1737155c4-Cl-C6H4Me4-Cl-C6H43

168-170 [19]169-1716755d4-Cl-C6H4Et4-Cl-C6H44

163-165 [23]163-1658235e4-F-C6H4Me4-F-C6H45

172-174 [19]173-1757535f4-F-C6H4Et4-F-C6H46

155-156 [15]154-1568165gPhMePh7

138-140 [21]140-1427465hPhEtPh8

177-178 [15]177-1798535i4-Me-C6H4Me4-Me-C6H49

131-132 [21]129-1317735j4-Me-C6H4Et4-Me-C6H410

175-177 [19]173-1756945k4-Br-C6H4Me4-Br-C6H411

169-171 [21]167-1696745l4-Br-C6H4Et4-Br-C6H412aIsolated yield.

Comparison of catalytic ability some of

catalysts reported in the literature for synthesis

of polysubstituted dihydro-2-oxypyrroles

are shown in Table 4. This study reveals that

Vanadium (V) oxide has shown its extraordinary

potential to be an alternative efficient and

inorganic catalyst for the one-pot synthesis of

these heterocyclic compounds, in addition to

good yields and short reaction times are the

notable advantages this present methodology.

ReferencesTime/Yield (%)ConditionsCatalystEntry

[20]1 h/82MeOH, r.t.I21

[23]3h/85MeOH, r.t.InCl32

[24]4 h/88MeOH, r.t.[n-Bu4N][HSO4]3

[25]5 h/81MeOH, r.t.Al(H2PO4)34

[27]6 h/91MeOH, r.t.Cu(OAC)2.H2O5

[29]4 h/84MeOH, r.t.ZrCl46

This work6 h/81MeOH, r.t.V2O57aBased on the four-component reaction of aniline, dimethylacetylenedicarboxylate, formaldehyde.


Conclusion

In summary, in this protocol, the use of

vanadium (V) oxide as an inorganic, mild

and efficient catalyst for the one-pot, four-

component synthesis of polysubstituted

dihydro-2-oxypyrrole from starting materials

is reported. Some advantages this methodology

are using of mild and non-toxic catalyst,

inexpensive, eco-friendly, environmentally

benign nature, short reaction times with no

column chromatographic separation and good

to high yields.

Acknowledgments

We gratefully acknowledge financial support

from the research council of the university of

Sistan and Baluchestan.

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One-pot Synthesis of Polysubstituted Dihydro-2- oxypyrroles …jacr.kiau.ac.ir/article_527186_4f621a6e88516fd2b8485bca4... · 2020-06-23 · low-cost, eco-friendly, one-pot, simple